5.5.1 The elderly
The term elderly is used arbitrarily to describe different age groups. Although 65 years has been the traditional cut-off, with an ageing population a cut-off set at 75 or even 80 years would seem more appropriate. Beyond biological age, co-morbidities and associated conditions such as frailty, cognitive and functional impairment, and physical dependence should be considered.
In European registries of NSTE-ACS, 27 – 34% of patients are aged .75 years.228,229 Despite the high proportion of elderly patients in registries, the elderly (.75 years) represent not more than 20% of all patients in recent trials of NSTE-ACS. Even when elderly patients are recruited into clinical trials, those randomized have substantially less co-morbidity than patients encountered in daily clinical practice.230Thus the applicability of findings from clinical trials to elderly patients encountered in routine clinical practice may be questionable.
Diagnosis and risk stratification in the elderly
The clinical presentation of NSTE-ACS in the elderly is often atypical and they are more likely to have mild symptoms.15 Among elderly patients with atypical presentation of NSTE-ACS, dyspnoea is the leading symptom, while syncope, malaise, and confusion are less frequent. The results of an ECG are less likely to demonstrate marked ST-segment deviation. Elderly patients present more frequently with NSTE-ACS than STEMI.
Age is one of the most important predictors of risk in NSTE-ACS.50 Patients aged .75 years have at least double the mortality rate of those,75 years. The prevalence of ACS-related complications such as heart failure, bleeding, stroke, renal failure, and infections markedly increases with age.
Therapeutic considerations
The elderly are at higher risk of side effects from medical treat- ment. This is particularly true for the risk of bleeding with antipla- telet agents and anticoagulants, but also for hypotension, bradycardia, and renal failure. In addition to the intrinsic bleeding risk of the elderly, older patients are more frequently exposed to excessive dose of antithrombotic drugs that are excreted by the kidney.231
The risk of major bleeding associated with unfractionated heparin, enoxaparin, GP IIb/IIIa receptor inhibitors, and P2Y12
inhibitors is significantly increased in older patients. In the SYNERGY trial, no difference in the rates of 30-day death or MI, 30-day death, and 1-year death between UFH and enoxaparin groups was observed among patients .75 years of age.
However, the rates of TIMI major bleeding and GUSTO severe bleeding were significantly higher in the enoxaparin group. As a
consequence, enoxaparin should be used with caution in the elderly and the dose should be adapted to renal function. Over 75 years of age, the dose should be reduced to 1 mg/kg once daily and anti-Xa activity monitored.232 A significantly lower risk of bleeding was observed with fondaparinux compared with enoxaparin in patients.65 years of age in the OASIS-5 trial.175
Elderly patients are substantially less likely to undergo an inva- sive strategy after NSTE-ACS. However, reports from individual trials suggested that the benefit from the invasive strategy was mainly observed in patients.65 years of age.233,234In a subgroup analysis of the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)- TIMI 18 trial, patients.75 years of age with NSTE-ACS derived the largest benefit, in terms of both relative and absolute risk reductions, from an invasive strategy at the cost of an increase in risk of major bleeding and need for transfusions.235 This was confirmed by a recent meta-analysis.209
Decisions on how to manage individual elderly patients should be based on ischaemic and bleeding risk, estimated life expectancy, co-morbidities, quality of life, patient wishes, and the estimated risks and benefits of revascularization.
5.5.2 Gender issues
Women presenting with NSTE-ACS are older than men and have a higher frequency of diabetes, hypertension, heart failure, and other
Recommendations for elderly patients
Recommendations Classa Levelb RefC Because of the frequent
atypical presentation, elderly patients (>75 years) should be investigated for NSTE-ACS at low level of suspicion
I C 15, 230
Treatment decisions in the elderly (>75 years) should be made in the context of estimated life expectancy, co-morbidities, quality of life, and patient wishes and preferences.
I C 230
Choice and dosage of antithrombotic drugs should be tailored in elderly patients to prevent the occurrence of adverse effects.
I C 230
Elderly patients should be considered for an early invasive strategy with the option of possible revascularization, after careful weighing up of the risks and benefits.
IIa B 233–235
aClass of recommendation.
bLevel of evidence.
cReferences.
NSTE-ACSẳnon-ST-elevation acute coronary syndrome.
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co-morbidities.236–238 Atypical presentation, including dyspnoea or symptoms of heart failure, is more common.228,239 Despite the differences in baseline risk, women and men with NSTE-ACS have a similar prognosis except in the elderly when women appear to have a better prognosis than men. This may be partially explained by the higher prevalence of non-obstructive CAD found on angiography in women.238 On the other hand, women with NSTE-ACS have a higher bleeding risk than men.
Therapeutic considerations
Although no sex-specific treatment effect has been described for most therapeutic agents, women with NSTE-ACS are less likely than men to receive evidence-based therapies including invasive diagnostic procedures and coronary revascularization.236,237,240
Contradictory results have been published with respect to the influence of sex on the treatment effect of an invasive strategy in NSTE-ACS. While observational studies suggested better long- term outcomes in unselected women undergoing an early invasive strategy, a meta-analysis showed that the benefit of invasive strat- egies was restricted to male patients, with no benefit in women up to 1 year of follow-up.241 Moreover, a number of randomized trials233,242 revealed a higher rate of death and non-fatal MI among women with NSTE-ACS undergoing an early invasive strat- egy. A significant sex interaction was also found in the FRISC-2 trial during the 5-year follow-up period, in which an invasive strategy showed a significant improvement in the reduction of death or MI in men but not in women.234
The meta-analysis by the Cochrane collaboration pointed out that women derive a significant long-term benefit in terms of death or MI (RR 0.73; 95% CI 0.59 – 0.91) for an invasive vs. con- servative strategy, although with an early hazard.243Some studies suggest that only in high risk female patients, such as those with troponin elevation244or with multivessel disease, is an early inva- sive strategy beneficial. Parallel findings have been described for the use of GP IIb/IIIa receptor inhibitors in women.245In fact, in a cohort of 35 128 patients with angiographic data, taken from a pooled analysis of 11 trials, 30-day mortality in women was not significantly different from that in men, regardless of ACS type, after adjustment for angiographic disease severity. Sex-based differ- ences in 30-day mortality observed among ACS patients are mark- edly attenuated after adjustment for baseline characteristics, angiographic findings, and treatment strategies.246
Thus, the data suggest that a routine early invasive strategy should be considered in women on the same principles as in men, i.e. after careful risk stratification for both ischaemic and bleeding risks including clinical and ECG evaluation, analysis of bio- markers, co-morbidities, and use of risk scores (see Section 4).
5.5.3 Diabetes mellitus
Approximately 20 – 30% of patients with NSTE-ACS have known diabetes, and at least as many have undiagnosed diabetes or impaired glucose tolerance.247 The Euro Heart Survey revealed that 37% of patients with NSTE-ACS had established or newly dis- covered diabetes.248 Patients with diabetes are older, are more often female, have more co-morbidities such as hypertension and renal failure, are more likely to present with atypical symp- toms, and are more prone to develop complications, particularly heart failure and bleeding.248
Diabetes mellitus is an independent predictor of mortality among patients with NSTE-ACS. Patients with diabetes have a two-fold higher risk of death.249,250 In addition, patients with impaired glucose tolerance or impaired fasting blood glucose have a worse prognosis than patients with normal glucose metab- olism, but a better prognosis than patients with confirmed diabetes.
Hyperglycaemia on admission or later during the hospital course is a strong independent marker of adverse prognosis in ACS whether or not the patient is diabetic, and may even be a stronger marker of risk than diagnosed diabetes.251
Therapeutic considerations
Registries have consistently shown that patients with NSTE-ACS and diabetes are at a higher risk for short- and long-term cardio- vascular events, but also that they are suboptimally treated com- pared with non-diabetic patients. In the European registries, revascularization (any form), thienopyridines, and GP IIb/IIIa recep- tor inhibitors were prescribed less frequently among diabetic patients than among non-diabetic patients, with a clear impact on in-hospital and long-term mortality (5.9% vs. 3.2% at 1 month, and 15.2% vs. 7.6% at 1 year). In addition, diabetic patients are less likely to receive reperfusion therapies or undergo revascular- ization compared with non-diabetic patients.248,250
Diabetics are high risk patients, and as such require aggressive pharmacological as well as invasive management. In addition, a comprehensive approach to secondary prevention should include pharmacological therapy and lifestyle changes.252
Data on the value of tight glycaemic control in MI are inconclu- sive.251In STEMI patients, tight glycaemic control using i.v. insulin was shown in Diabetes, Insulin Glucose Infusion in Acute Myocar- dial Infarction (DIGAMI) to reduce 1-year mortality by 30%, but this was not confirmed in DIGAMI-2. In predominantly stable patients with diabetes and also in intensive care units, recent studies have not shown improved outcomes with tight glycaemic control, but rather an excess of events related to more frequent hypoglycaemic episodes in patients allocated to tight blood glucose control.253 Until more data become available the treat- ment target should be to avoid severe hyperglycaemia [glucose concentration .10 – 11 mmol/L (.180 – 200 mg/dL)] as well as hypoglycaemia [,5 mmol/L (,90 mg/dL)]. There is no evidence Recommendations for gender
Recommendations Classa Levelb RefC Both genders should be
evaluated and treated in the same way.
I B 246
aClass of recommendation.
bLevel of evidence.
cReference.
NSTE-ACSẳnon-ST-elevation acute coronary syndrome.
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that glucose – insulin – potassium improves outcome, but may be even deleterious.254
Revascularization in diabetic patients causes specific problems.
CAD is typically diffuse and extensive, and restenosis as well as occlusion rates after PCI and CABG are higher. Repeat revascular- ization procedures are more frequent after PCI, compared with CABG. An early invasive approach has been shown to be beneficial in this high risk subgroup, with greater benefit in diabetic than in non-diabetic patients.255
In unselected diabetic patients with multivessel disease, CABG appears to offer a better outcome compared with PCI. In a meta-analysis of individual data from 7812 patients in 10 random- ized trials, CABG was associated with significantly lower mortality at 5.9-year follow-up than with PCI in diabetic patients.256Overall there was no difference in mortality with CABG vs. PCI (15% vs.
16%; HR 0.91; 95% CI 0.82 – 1.02;Pẳ0.12), but mortality was sig- nificantly lower for CABG among 1233 patients with diabetes [23% vs. 29%; HR 0.70; 95% 0.56 – 0.87; Pẳ0.05; numbers needed to treat (NNT)ẳ17]. In the Bypass Angioplasty Revascu- larization Investigation 2 Diabetes (BARI-2D) trial, diabetic patients with stable angina were randomized to either intensive medical therapy or intensive medical therapy plus revasculariza- tion with either CABG or PCI (physician’s choice). At 5-year follow-up, in 763 patients in the CABG group, the rates of all- cause mortality or MI were significantly lower in the CABG group vs. intensive medical therapy alone (21.1% vs. 29.2%; P ,0.010), as well as the rate of cardiac death or MI (15.8% vs.
21.9%; P ,0.03) and MI (10% vs. 17.6%;P ,0.003). There was no significant difference in outcome between intensive medical therapy alone and intensive medical therapy plus PCI.257,258 In SYNTAX—a trial comparing CABG with PCI with DESs in main stem and multivessel disease—the difference in major adverse cardiac and cerebral events at 1-year follow-up between CABG and PCI groups was doubled in the pre-defined diabetes cohort, mostly driven by repeat revascularization.259 However, there was no significant difference in rates of death or MI.
Finally, in the New York Registry, a trend to improved outcomes in diabetic patients treated with CABG compared with DESs (OR for death or MI at 18 months 0.84; 95% CI 0.69 – 1.01) was reported.260
All of these studies suggest that CABG offers a better outcome compared with PCI in diabetic patients. However, it has to be pointed out that these trials incorporated mostly—if not only—
chronic stable patients, and it is unclear whether these data can be extrapolated to patients with NSTE-ACS.
With respect to the choice of stent, in a meta-analysis a DES proved to be at least as safe as a BMS provided that DAPT is con- tinued for .6 months, which is indicated in ACS anyway.261 Repeat target vessel revascularization was considerably less fre- quent with a DES than a BMS (OR 0.29 for sirolimus eluting;
0.38 for paclitaxel eluting). It may be assumed that this is similar in diabetic patients with ACS. Regarding the choice of conduits, observational studies suggest that arterial grafts offer better outcome compared with saphenous vein grafts. The impact of revascularization with bilateral arterial grafting on long-term outcome and risk of mediastinal infections is still debated. Again, no data confined to ACS patients alone are available.
There is no indication that the antithrombotic regimen should differ between diabetic and non-diabetic patients. However, in the TRITON-TIMI 38 trial, prasugrel was shown to be superior to clopidogrel in reducing the composite endpoint of cardiovascu- lar death or MI or stroke without excess major bleeding.262Simi- larly, ticagrelor, when compared with clopidogrel in the PLATO trial, reduced the rate of ischaemic events in ACS patients irrespec- tive of diabetic status and glycaemic control, without an increase in major bleeding events.263Ticagrelor reduced all-cause mortality in patients with haemoglobin A1c above the median (.6%).
Although GP IIb/IIIa receptor inhibitors were shown in an earlier meta-analysis (without concomitant use of thienopyridines) to have a favourable impact on outcome in diabetic patients,264 routine upstream treatment was not confirmed to be beneficial in the more recent EARLY-ACS trial.151 Therefore, with the current use of high dose oral antiplatelet agents, diabetic patients
Recommendations for diabetic patients
Recommendations Classa Levelb RefC All patients with NSTE-
ACS should be screened for diabetes. Blood glucose levels should be monitored frequently in patients with known diabetes or admission hyperglycaemia.
I C -
Treatment of elevated blood glucose should avoid both excessive hyperglycaemia [10–11 mmol/L (>180–200 mg/dL)] and hypoglycaemia [<5 mmol/L (<90 mg/dL)].
I B 251, 253
Antithrombotic treatment is indicated as in non-diabetic patients.
I C -
Renal function should be closely monitored following contrast exposure.
I C -
An early invasive strategy is
recommended. I A 233, 255
DESs are recommended to reduce rates of repeat revascularization.
I A 148, 261
CABG surgery should be favoured over PCI in diabetic patients with main stem lesions and/or advanced multivessel disease.
I B 259
aClass of recommendation.
bLevel of evidence.
cReferences.
CABG, coronary artery bypass graft; DESẳdrug-eluting stent; NSTE-ACS, non-ST-segment elevation acute coronary syndromes; PCI, percutaneous coronary intervention.
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do not seem to benefit from the routine addition of GP IIb/IIIa receptor inhibitors.
Prevention of contrast-induced nephropathy is particularly important in diabetic patients undergoing angiography and/or PCI (see Section 5.5.4). There are no data to support delay of angiogra- phy in patients treated with metformin as the risk of lactate acido- sis is negligible.265 Renal function should be monitored closely following contrast exposure.
5.5.4 Chronic kidney disease
Renal dysfunction is present in 30 – 40% of patients with NSTE-ACS.266,267 Kidney function is best assessed with eGFR according to the MDRD equation, which includes ethnicity and sex in its calculation. It should be calculated in all patients with or at increased risk of chronic kidney disease (CKD). In daily clini- cal practice, however, CrCl calculated with the Cockroft – Gault formula may also be used. For definitions of CKD, see the previous guideline.3
Patients with CKD more frequently present with heart failure and without typical chest pain.268 Patients with NSTE-ACS and CKD often do not receive guideline-recommended therapy.
CKD is associated with a very adverse prognosis,266,268 and is an independent predictor of short- and long-term mortality and of major bleeding in patients with NSTE-ACS.267
Therapeutic considerations
Despite the fact that patients with NSTE-ACS and CKD are fre- quently under-represented in clinical trials, there is no particular reason not to treat these patients just like patients devoid of renal dysfunction. However, caution is needed with respect to the antithrombotic treatment in terms of bleeding compli- cations.168,269,270
Registry data show that CKD patients are often overdosed with antithrombotics, particularly anticoagulants and GP IIb/IIIa receptor inhibitors, and are therefore more prone to bleed. Many drugs with exclusive or substantial renal elimination need to be down-titrated or might even be contraindicated in CKD patients, including enoxaparin, fondaparinux, bivalirudin, and small-molecule GP IIb/IIIa receptor inhibitors (Table 10). In the case of severe renal failure, when fondaparinux or enoxaparin are contraindicated, UFH should be used. However, in the GRACE registry UFH did not protect against bleeding complications, and a gradual increase in the risk of bleeding with declining renal function was observed with UFH, similar to that observed with LMWH.269 The advantages of UFH over other anticoagulants in CKD patients are that its anticoagulant activity is easily monitored with aPTT, and it can be quickly neutralized in the event of bleeding. Fondaparinux has a much safer profile than enoxaparin in CKD, as shown by the much lower risk of bleeding complications observed in OASIS-5 with fondaparinux compared with enoxaparin. Ticagrelor com- pared with clopidogrel in the PLATO trial significantly reduced ischaemic endpoints and mortality without a significant increase in major bleeding, but with numerically more non-procedure- related bleeding.271
Data on the impact of an invasive strategy on clinical endpoints in patients with NSTE-ACS and CKD are not available, as many trials of revascularization in NSTE-ACS excluded patients with CKD. In a large registry as well as in substudies of trials in the
setting of NSTE-ACS, the outcome of CKD patients improved with invasive management, not only at end-stage renal failure but also at the stage of moderate CKD. In observational studies an early invasive therapy is associated with better 1-year survival in patients with mild to moderate renal insufficiency, but the benefit decreases with worse renal function, and is uncertain in those with renal failure or on dialysis.
Patients with CKD are at risk of contrast-induced nephropathy.
This risk is increased in patients with older age and diabetes. In the case of urgent angiography the risk of contrast-induced nephropa- thy must be balanced against the ischaemic risk. Hydration before (12 h) and following (24 h) angiography and/or angioplasty is the strategy that has been shown to have the greatest impact in redu- cing the risk of this nephropathy. The amount of contrast should
Table 10 Recommendations for the use of antithrombotic drugs in CKD
Drug Recommendations
Clopidogrel No information in patients with renal dysfunction.
Prasugrel No dose adjustment necessary, including in patients with end-stage disease.
Ticagrelor No dose reduction required; no information in dialysis patients.
Enoxaparin
Dose reduction to 1 mg/kg once daily in the case of severe renal failure (CrCl <30 mL/min).
Consider monitoring of anti-Xa activity.
Fondaparinux Contraindicated in severe renal failure (CrCl <20 mL/min). Drug of choice in patients with moderately reduced renal function (CrCl 30–60 mL/min).
Bivalirudin
Patients with moderate renal impairment (30–59 mL/min) should receive an infusion of 1.75 mg/kg/h. If the creatinine clearance is
<30 mL/min, reduction of the infusion rate to 1 mg/kg/h should be considered. No reduction in the bolus dose is needed. If a patient is on haemodialysis, the infusion rate should be reduced to 0.25 mg/kg/h.
Abciximab
No specific recommendations for the use of abciximab, or for dose adjustment in the case of renal failure. Careful evaluation of haemorrhagic risk is needed before using the drug in the case of renal failure.
Eptifibatide
The infusion dose should be reduced to 1 àg/kg/min in patients with CrCl <50 mL/min.
The dose of the bolus remains unchanged at 180 àg/kg. Eptifibatide is contraindicated in patients with CrCl <30 mL/min.
Tirofiban
Dose adaptation is required in patients with renal failure; 50% of the bolus dose and infusion if CrCl is <30 mL/min.
Recommendations for the use of drugs listed in this table may vary depending on the exact labelling of each drug in the country where it is used.
CrClẳcreatinine clearance.
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